Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors.

Bladder cancer is a malignant tumor with a high incidence and mortality worldwide. Clinically, DNA-damaging agents such as cisplatin, irinotecan, and gemcitabine are commonly used, but their efficacy is often limited by acquired resistance. A key resistance mechanism involves the upregulation of PARP1 in response to drug-induced DNA single-strand breaks (SSBs), which diminishes the therapeutic effect. To overcome this obstacle, we designed and synthesized a series of united TOP1/PARP1 inhibitors that simultaneously induce SSBs via TOP1 inhibition and block their repair via PARP1 inhibition, converting repairable SSBs to lethal double-strand breaks (DSBs). Among these, compound D5 exhibited excellent dual-target inhibitory activity and effectively overcame cisplatin resistance, demonstrating potent antitumor efficacy in vitro and in vivo (TGI = 65.7%). Collectively, D5 represents a promising TOP1/PARP1 inhibitor for overcoming resistance to conventional DNA-damaging chemotherapies.